Tiratricol treatment of children with Monocarboxylate Transporter 8 deficiency: Triac Trial II

In this trial, the effect of tiratricol on neurodevelopment of patients with
MCT8 deficiency (also called Allan-Herndon-Dudley syndrome) will be studied.
MCT8 deficiency is caused by pathogenic mutations in the MCT8 encoding gene
SLC16A2.
Monocarboxylate transporter (MCT)8 is a transporter protein, highly specific
for thyroid hormones (both the inactive prohormone T4 as the active hormone
T3). In the human body MCT8 plays an important role in transport of thyroid
hormone into different tissues. Previous research has shown that MCT8 is
especially crucial in transport of thyroid hormones over the blood-brain
barrier and into neuronal cells.
Defective MCT8 (caused by mutations in SLC16A2, called MCT8 deficiency) results
in a lack of thyroid hormone into the brain and therefore, a shortage of
thyroid hormone in the brain. This hypothyroid state of the brain leads to a
combination of severe developmental delay and severe mental retardation.
Together, this clinical picture is called the neurocognitive phenotype of MCT8
deficiency.
Characteristic for these patients are high concentrations of circulating active
thyroid hormone (T3), due to several alterations in the
hypothalamus-pituitary-thyroid axis. In contrast to the central nervous system,
large parts of the body are independent of MCT8 for thyroid hormone transport,
resulting in high concentrations of thyroid hormone reaching several target
organs and thus a hyperthyroid state in these organs. Patients show amongst
others muscle wasting, tachycardia and liver enzyme abnormalities, together
called the peripheral phenotype of MCT8 deficiency.
Tiratricol is an analogue of T3 and has many similarities to T3. However, there
is one major difference: Tiratricol is independent of MCT8 for transport. With
this property, tiratricol is a good candidate to a) relieve the cerebral
hypothyroid state and b) suppress the high circulating T3 concentration and the
peripheral phenotype caused by it.
A recent international multicenter trial showed that tiratricol is able to
suppress the peripheral phenotype in a safe manner. The effect of tiratricol
treatment initiated at a young age on the neurocognitive phenotype remains to
be studied.

This study has been transitioned to CTIS with ID 2024-516123-13-00 check the CTIS register for the current data.

Part I:
Primary Objective:
Evaluate the effects of tiratricol on neurodevelopment in young MCT8 deficiency
patients, as measured by the Gross Motor Function Measure (GMFM)-88 and Bayley
Scales of Infant Development (BSID-III) Gross Motor Skill Domain.

Secondary Objectives:
1. Evaluate the effect of Tiratricol treatment at week 96 on specific motor
development milestones
2. Evaluate the effect of tiratricol treatment on neurodevelopment in young
MCT8 deficient patients as measured by BSID-III
3. Evaluate the effect of tiratricol at week 96 on clinical and biochemical
thyrotoxic features (serum T3 concentrations, tissue specific markers of
thyroid hormone action).

Exploratory objectives:
1. Evaluate the effects of tiratricol treatment on quality of life for patients
and parents.
2. Evaluate the effect of tiratricol treatment on neurological status.
3. Evaluate the effect of tiratricol treatment on brain function/brain imaging
(EEG, BERA, VEP and MRI/MRS) (optional).
4. Study the pharmacokinetic profile of tiratricol in young children
(optional)
5. Evaluate the effect of tiratricol on cardiovascular features of the
thyrotoxicosis.

Safety objective:
1. Evaluate the safety of tiratricol treatment in patients 0-30 months of age.

Part II
Primary Objective:
Evaluate the effects of long-term treatment (up to 4 years of total treatment)
with tiratricol on neurodevelopment in young boys (<=30 months) with MCT8
deficiency, as measured by the Gross Motor Function Measure (GMFM)-88 and
Bayley Scales of Infant Development (BSID)-III Gross Motor Skill Domain.
Secondary Objectives:
1. Evaluate the effect of long-term treatment (up to 4 years of total
treatment) with tiratricol on specific motor development milestones.
2. Evaluate the effect of long-term treatment (up to 4 years of total
treatment) with tiratricol as measured by the BSID-III.
3. Evaluate the long-term treatment effect (up to 4 years of total treatment)
of tiratricol on clinical and biochemical thyrotoxic features (serum T3
concentrations, tissue specific markers of thyroid hormone action).
Exploratory objectives:
1. Evaluate the effect of tiratricol treatment on neurological status.
2. Study the pharmacokinetic profile of tiratricol in young children (optional).
Safety objective:
1. Evaluate the safety of long-term tiratricol treatment.

In this open label phase II study, we will investigate the effect of treatment
with tiratricol in young boys (<=30 months) with MCT8 deficiency. The hypothesis
tested is that treatment with tiratricol will have a beneficial effect on the
hypothyroid state in the brain as well as the hyperthyroid state in peripheral
organs and tissues in these patients. Patients will be treated for 96 weeks
with tiratricol, treatment effect on neurodevelopment impairment caused by
hypothyroidism and peripheral thyrotoxicosis will be evaluated after 96 weeks
treatment. An interim analysis will be done after 48 weeks treatment. As a
result of the interim analysis, the study may be adapted in terms of dosing,
duration or sample size.

After the 96 week treatment period, patients will enter Part II of the trial,
evaluating long-term treatment. Patients will be followed for an additional 2
years and treatment effect will be evaluated after 3 years and 4 years
respectively from start of treatment.

Tiratricol will be administered, to all patients, orally or through feeding
tube in an individual dose titrated based on serum T3 response.
The dose will be divided into 1-3 administrations per day.

Participation in this study will pose a burden of approximately 15 extra visits
to the hospital, of which the majority will be short control visits (consisting
of physical examination and drawing blood). At the start of the study, after
one year of treatment and at the end of the study there will be an extensive
evaluation including extensive neurological and cardiological examinations. The
extra visits are spread over a time window of two years.
Many control visits will coincide with appointments for regular care. All study
procedures, except for vena punctures/finger pricks, are non-invasive and have
no physical or emotional risk for patients. Vena punctures/finger pricks are
minimally invasive and have only mild risks.
During the whole study period Part I at most 4-5 and during Part II 4
additional vena punctures will be required.
There is worldwide experience with tiratricol as a treatment for rare thyroid
disorders, also in treatment of children. Side effects of tiratricol are mainly
dose related and consist of symptoms of hyperthyroidism. Overdosing will be
prevented by close follow-up and evaluation of recruited patients and by
applying individual dose titration. Side effects are transient and will subside
within two days after dose reduction.
Given the scope of the study, it has to be conducted in young patients with
MCT8 deficiency.
The potential benefits of tiratricol treatment are listed in the background
section above.